With the rising epidemic of tuberculosis (TB) in developing countries and the increase in resistant TB strains appearing world-wide, there is an urgent need to discover and develop new anti-TB drugs. An innovative approach of using bioengineered bacteria (E. coli) as sources of novel molecules has succeeded in the identification of a series of compounds exhibiting anti-TB activities in our cellular assays. Structure elucidation of one of these active series has shown it to possess a flat heterocyclic core of low molecular weight and solubility. Our goal is to advance this series to the drug development level by 1) identifying a chemical synthetic approach to these isolates amenable for access to gram quantities, 2) utilize our biological testing panel of anti-TB assays to identify the most promising and selective lead compound, 3) optimize the bioactivity, safety, and stability of this lead via further chemical modification of the molecule. PUBLIC HEALTH RELEVANCE: One third of the world's population is infected with the bacteria Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), with approximately 1/2 million cases of drug-resistant TB of which 6.6% of these being extensively drug resistant (X- DR TB). The present drug therapies which originated over 50 years ago can no longer be expected to limit this epidemic. Using a genetically engineered E.coli bacteria to oxidatively metabolize simple chemical starting materials, we have isolated a novel series of anti-TB agents. This series will be modified via organic chemistry leading to the development of a novel, orally active anti-TB drug.